Reproductive Hormones

Nonsense mutation in STAR that abolishes steroidogenic acute regulatory protein function; the most prevalent allele causing lipoid congenital adrenal hyperplasia, accounting for approximately 70% of cases globally — homozygotes have near-complete loss of all steroid hormone synthesis

Pathogenic missense variant in CYP17A1 causing complete loss of 17α-hydroxylase/17,20-lyase activity; homozygotes develop 17α-hydroxylase deficiency (hypertension, hypokalemia, and sexual infantilism), while heterozygous carriers show subclinical enzyme reduction detectable by ACTH stimulation testing.

Pathogenic nonsense variant in CYP17A1 introducing a premature stop codon at position 239 (c.715C>T); homozygotes or compound heterozygotes develop complete 17α-hydroxylase/17,20-lyase deficiency with hypertension, hypokalemia, absent pubertal development, and adrenal crisis risk.

Missense variant in CYP17A1 reducing both 17α-hydroxylase and 17,20-lyase activities to 40–45% of normal; causes partial combined 17α-hydroxylase/17,20-lyase deficiency with variable sex steroid deficiency, mineralocorticoid excess, and impaired fertility

Pathogenic missense variant abolishing 17α-hydroxylase/17,20-lyase activity, causing combined cortisol and sex steroid deficiency with mineralocorticoid excess

Rare pathogenic nonsense variant in CYP17A1 causing complete abolition of 17α-hydroxylase/17,20-lyase activity; homozygotes develop the full 17α-hydroxylase deficiency phenotype (hypertension, hypokalemia, absent puberty, low cortisol), while heterozygous carriers are clinically unaffected but carry a CYP17A1 loss-of-function allele relevant to reproductive planning.

Pathogenic CYP17A1 missense variant causing combined 17α-hydroxylase/17,20-lyase deficiency; homozygotes lose all sex steroid and cortisol synthesis, developing hypertension, hypokalemia, and absent puberty; heterozygous carriers are asymptomatic but carry reproductive risk

Pathogenic missense variant in CYP17A1 causing complete loss of 17α-hydroxylase/17,20-lyase activity; homozygotes develop 17α-hydroxylase deficiency (CAH) with absent sex steroids, primary amenorrhea, and mineralocorticoid excess; heterozygous carriers have subclinical steroid biosynthetic abnormalities and should undergo endocrinology evaluation

Intronic variant in estrogen receptor alpha associated with bone mineral density; the T allele is linked to lower BMD and may influence ESR1 expression in bone and reproductive tissues

Nonsense mutation in the TSHR gene (Trp546Ter) that eliminates functional TSH receptor expression; homozygotes develop severe congenital hypothyroidism; heterozygous carriers may have subclinical TSH elevation warranting monitoring

Intronic variant in SULT1E1 (estrogen sulfotransferase) associated with altered SULT1E1-related outcomes; the C allele, enriched in East Asian populations, has been linked to worse colorectal cancer survival and may influence local estrogen bioavailability through effects on SULT1E1 expression regulation

Pathogenic STAR variant that abolishes steroidogenic acute regulatory protein activity, causing lipoid congenital adrenal hyperplasia — the most severe form of CAH, with absent cortisol, aldosterone, and sex steroid production

STAR missense variant abolishing steroidogenic activity; homozygous carriers develop lipoid congenital adrenal hyperplasia with absent cortisol, aldosterone, and sex hormone production

Intronic variant in SRD5A2 tagging haplotype backgrounds that differ in 5-alpha-reductase type 2 activity; associated with sperm motility differences in normozoospermic men

Intronic variant in the aromatase gene associated with lower circulating estradiol and higher FSH levels; the A allele reduces aromatase activity and has been linked to higher sperm counts in men and lower bone mineral density

Intronic CYP19A1 polymorphism associated with variation in aromatase expression and androgen-to-estrogen conversion; the G allele is linked to lower aromatase activity and elevated androgen levels in reproductive tissues, with population-specific associations to PCOS risk

Intronic NR3C1 variant tagging glucocorticoid receptor gene haplotype blocks associated with cortisol sensitivity, HPA axis reactivity, and downstream effects on reproductive hormone regulation

3'UTR variant in estrogen receptor alpha that alters miR-453 binding affinity; the C allele strengthens microRNA-mediated ESR1 repression while the T allele weakens it, raising ESR1 protein levels and increasing premenopausal breast cancer risk

Intronic variant in the mineralocorticoid receptor gene associated with altered receptor signaling and modestly elevated risk of spontaneous preterm birth; the minor G allele shows protective effects are reduced compared to the common A allele

Missense variant abolishing 3β-hydroxysteroid dehydrogenase type 2 activity; homozygotes develop salt-wasting congenital adrenal hyperplasia, heterozygous carriers are clinically normal but can pass the allele to offspring

Intronic variant in the angiotensinogen (AGT) gene; the T allele has been incorporated into diastolic blood pressure prediction models and sits in a gene whose renin-angiotensin signaling role makes it a plausible contributor to blood pressure regulation during pregnancy, including gestational hypertension and preeclampsia susceptibility

Intronic variant in PDE8B (phosphodiesterase 8B) strongly associated with serum TSH levels; each A allele raises TSH by ~0.13 mIU/L through reduced cAMP degradation in thyroid tissue, with consequences for ovulatory function, implantation, and pregnancy maintenance

Regulatory variant in the CYP19A1 aromatase gene that alters estrogen biosynthesis, influencing circulating estradiol levels, bone mineral density, and response to aromatase inhibitor therapy.

Intergenic GWAS variant on chromosome Xp22, near the testis-specific genes FAM9B and FAM9A, associated with serum testosterone levels in men; the C allele is linked to higher testosterone and the T allele (major) to lower testosterone

Synonymous coding variant in CYP17A1 that tags a haplotype linked to altered DHEA-S levels and steroid production; associated with prostate cancer progression and castration-resistant prostate cancer risk

Missense variant in SHBG exon 8 (p.Asp356Asn, historically Asp327Asn in mature-protein numbering) that adds an N-linked glycosylation site to the C-terminal domain, increasing SHBG serum half-life and circulating SHBG levels; the A allele is associated with higher total SHBG, lower free-androgen index, and a protective effect against PCOS and metabolic syndrome, but with worse prostate cancer outcomes during androgen deprivation therapy.

Coding variant in aromatase that substitutes cysteine for arginine at position 264; in vitro evidence shows increased aromatase activity, with reported associations with PCOS risk and ART pregnancy outcomes in some populations

Intronic variant near the CYP19A1 promoter region, falling within MIR4713HG but mapping to the CYP19A1 RefSeqGene locus; associated with breast cancer histological grade and tumor size in a Swedish cohort, consistent with its position in the aromatase regulatory zone

Regulatory variant 1 kb downstream of the SHBG gene that reduces sex hormone-binding globulin levels; the T allele lowers SHBG by ~10–20%, increasing free testosterone and free estradiol bioavailability and elevating risk for PCOS and androgen-driven metabolic dysfunction.

Intronic eQTL variant in the aromatase gene CYP19A1; the minor C allele is the strongest common genetic determinant of lower circulating estradiol in postmenopausal women, acting through altered aromatase expression in peripheral tissues.

Deep intronic variant in the testosterone-to-DHT converting enzyme; the minor T allele is associated with higher serum DHT levels, with implications for androgenetic alopecia severity, prostate growth, and response to 5-alpha-reductase inhibitors

Pathogenic missense variant in CYP17A1 disrupting the heme-binding region of the enzyme, abolishing both 17α-hydroxylase and 17,20-lyase activity; the most common CYP17A1 mutation in East Asian populations (Chinese, Japanese, Korean); homozygotes develop combined 17α-hydroxylase/17,20-lyase deficiency with cortisol deficiency, sex steroid absence, and mineralocorticoid excess causing hypertension

Pathogenic nonsense variant introducing a premature stop codon at position 171 of 3β-hydroxysteroid dehydrogenase type II, abolishing conversion of Δ5-steroids to Δ4-steroids in adrenal glands and gonads; homozygotes develop severe salt-wasting congenital adrenal hyperplasia with deficiency of cortisol, aldosterone, and sex steroids.

Intronic variant within the SHBG gene that participates in a haplotype (with rs727428) lowering circulating sex hormone-binding globulin levels, increasing bioavailable testosterone and estradiol; lower SHBG is linked to PCOS susceptibility, insulin resistance, type 2 diabetes risk, and female VTE risk mediated by estradiol

Intronic variant in the estrogen receptor alpha gene (intron 1) associated with endometriosis-related infertility, IVF outcomes, severe pre-eclampsia risk, and ovarian reserve; the G allele increases endometriosis-related reproductive risk while showing some population-specific protective effects for fractures and male fertility